Derivatives of 5h-dibenzo[a, d] cycloheptene



United States Patent 3,264,342 DERIVATIVES 0F H=DIBENZO[a,d]CYCLOHEPTENE Walter Schindler, Riehen, near Basel, Switzerland, assignorto Geigy Chemical Corporation, Artisley, N.Y., a corporation of DelawareNo Drawing. Original application May 24, 1963, Ser. No. 282,874. Dividedand this application Jan. 21, 1965, Ser. No. 432,931 Claims priority,application Switzerland, Mar. 14, 1961, 3,054/ 61 4 Claims. (Cl.260-471) This application is a division of copending application SerialNo. 282,874, filed on May 24, 1963, which is a continuation-in-part ofmy pending application Serial No. 179,482 filed on March 13, 1962 (nowabandoned).

The aforesaid copending application, Serial No. 282,- 874, relates toderivatives of 5H dibenzo[a,d] cycloheptene corresponding to the generalFormula I wherein X is an ethylene (CH CH or vinylene (CH=CH-) radical,and their non-toxic acid addition salts with pharmaceutically acceptableinorganic and organic acids, which have valuable pharmacologicalproperties. In particular, they antagonize the action of serotonin andof reserpine; they are also spasmolytic and decontracting, and, to alesser extent, they are antihistaminic.

According to the said application, Serial No. 282,874, compounds I areprepared by a process which comprises (a) Reacting a tertiary amine ofthe formula CHT-CHPCIIz-N R (II) wherein R represents a benzyl radical,a lower alkenyl radical or, most advantageously, a lower alkyl radicalwhich latter is preferably the methyl radical, and

X has the meaning given, above,

with a carbonic acid halide which is a compound in which the onehydroxyl group of the carbonic acid molecule is replaced by eitherchlorine or bromine and the other hydroxyl group of the carbonic acidmolecule is replaced by lower alkyl, especially methyl, llower alkoxy,benzyloxy, phenyl or chlorine, and of which there are preferredchloroformic acid esters, especially the lower alkyl esters such aschloroformic acid methyl ester, ethyl ester, or the benzyl ester,furthermore phosgene, a lower alkanoic acid halide such as acetylchloride or bromide, or benzoyl chloride, in the presence or absence ofa suitable inert organic solvent such as, preferably, benzene, toluene,carbon tetrachloride, but also diethyl ether, diisopropyl ether ortetrahydrofuran, at room temperature (+20" C.) or at elevatedtemperature, up to about 110 C., preferably in the range of 40 to 110 C.The acid halides can be employed in equirnolar amount or in aconsiderable excess and may serve in the latter case, as sole reactionmedium. The reaction is exothermic and the benzyl, alkenyl or alkylhalide containing the radical R is liberated. If needed, the reactioncan be performed or completed with heating:

(b) Hydrolyzing the resulting compound of the formula wherein Acrepresents lower alkanoyl, especially acetyl, lower alkoxycarbonyl,benzyloxycarbonyl, chlorocarbonyl, or lower alkanoyl, in particular CHOCO-, C H OCO, C H CH OCO and ClCO-, and

X has the meaning given above,

hydrolysis being carried out at an elevated temperature ranging from 60to 0, either in higher boiling organic solvents containing hydroxylgroups such as, e.g., ethylene glycol, diethylene glycol or themono-lower alkyl ethers thereof, or in lower alkanols; in the lattercase, the treatment may be performed in a closed vessel.

Lower as used in this specification and the appended claims inconnection with alkyl means maximally 6 and preferably 1 to 3 carbonatoms; in connection with alkoxy and alkanoyl it means 1 to 4, and inconnection with alkenyl it means maximally 6, preferred alkenyl radicalsbeing allyl and crotyl.

The crude hydrolysis product from step (b) is then further processed asdescribed in said application, and compounds of Formula I are obtainedin very good yield rates in the order of 70% and higher (calculated onthe weight of the corresponding compound of Formula II).

This is very surprising because it would have been expected that theunstable intermediate quaternary compound which is formed by the actionof the acid chloride on the tertiary amine would preponderantly (a) Bedecomposed due to the presence of the reactive allylic hydrogen atom toan unsymmetrically di-substituted butadiene and dialkyl alkanoyl amide,or

(b) In analogy with the teachings of Renk et al. in I.A.C.S., 83, 878(1961), give rise to the formation of a complex mixture of butylideneand/or butenyl chloride derivatives and a number of rearranged and/orring closed products.

In contrast to the pharmacodynarnic spectrum of 5- ('y dimethyl aminopropyllidene) 10,11 dihydro- SH dibenzo[a,d] cycloheptene, thecorresponding monomethylamino derivative of Formula I has apharmacodynamic spectrum with a strong antidepressive component and anattenuated antihistaminic component (very strong in the spectrum of thedimethyl amino compound), while the sedative component is negligible incontrast to that of the aforesaid dimethylamino compound.

A particularly effective process comprises taking a compound of theabove-defined Formula III, wherein AC is C2H5OCO--, Or CICO--, anddissolving Kit in a solvent such as ethylene glycol or/ and diethyleneor/ and diethylene glycol mono- (lower)alkyl ether, e.g., diethyleneglycol monoethyl ether, then hydrolyzing said compound at raisedtemperatures, e.g. from a temperature of about 50 degrees centigradebelow the boiling point of the solvent up to a temperature correspondingto the boiling point of said solvent and not exceeding 180 C.

The term hydrolysis as employed here embraces alkaline as well as acidhydrolysis followed by an automatic decarboxylation to yield compoundsof the abovedefined Formula I.

The reaction mixture obtained from hydrolysis step (b) is then processedin a conventional manner to recover the basic constituent, for instanceby evaporation of the solvent and/or dilution with water, extraction ofthe residue or aqueous solution with Water-immiscible extractants suchas chloroform, ether, benzene and the like, extracting the organic phasewith aqueous dilute acid,

basifying the aqueous acid extract and recovering the desired product.higher.

Yield rates are in the order of.80%' and Compounds of the Formula II arecommercial products; they are obtained, for example, by reaction of SHI-dibenzo[a,d]cycloheptene-Fone or 10,11-dihydro-5H-dibenzo[a,d]cycloheptene 5 one with a 'y-dialkylarninm propyl metalcompound, 7 (N.- alkyl alkenylamino)- propyl metal compound,-dialkenylamino-propyl metal.

compound or 'y (N alkyl-benzyl-amino)-propyl metal compound, inparticular with a -dimethylamino-propyl metalcompound, and thensplittingoif water. compounds are in particular magnesium organic, lithiumorganic and Zinc organic compounds: Preferably the corresponding organicmagnesium halide compounds are.

used which are produced in the known manner from N,N- disubstituted'y-amino-propyl Ihalides in diethyl ether, tetrahydrofuran or anotherethereal solvent. The. water is split ofi in the second step of thereaction very easily, for example, even on letting the tertiary hydroxylcom: pounds stand in concentrated aqueous alcoholic hydrochloric acid atroom temperature.

The compounds of the Formula I produced according to the invention formsalts, most of which are water. soluble, with inorganic and organicacids such. as hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, methane sulfonic acid, ethane disulfonic acid,,B-hydroxyethane sulfonic acid, acetic acid, succinic acid,

furnaric acid, maleic acid, .malic acid, tartaric acid, citric acid,benzoic acid, salicylic acid and mande-lic acid.

Pharmaceutical compositions of the novel compound of Formula I containthis compound or'non-toxic acid addition salts thereof admixed withpharmaceutically acceptable organic and/or inorganic solid or liquidcarriers I suitable for interal or parenteral administration. They areused, for instance, in the form of tablets, drages, capsulesor in liquidform as solutions, drops, suspensions or emulsions. Such compositionsand preparations contain at least 0.5% of the active compound ofFormula 1. Its percentage in these preparations and compositions, ofcourse, may be varied and may be between about 1% and about 50% or evenhigher of the total weight of a dosage unit. Preferred compositions andpreparations Suitable are prepared in such a manner that a dosage unitform contains between about 10 mg. and about 250 mg. of the: compound ofFormula I..

The following examples further illustrate the performance of the processaccording to the invention without in any Way limiting the invention tothis single: method. Parts are given therein as parts by Weight;theirrelatiomship to parts by volume is as that of grammesto cubiccentimetres. The temperatures are given in degrees centi-. grade: abs.means anhydrous; torr stands for mm. Hg.

Example 1 (a) 13.0 parts of 5-('y-dimethylamino-propylidene)-10,1l-dihydro-SH-ldibenzcda,d]-cycloheptene are dissolved in 100 partsby volume of abs. benzene and this solution is added dropwise Whilestirring strongly to 18 parts of chloroformic acid ethyl estern Thetemperature .rises to about35 and methyl chloride is developed. Thewholeis stirred for a further 1 /2 hours at 40. Aftereooling,

7.0 parts of water. and 50 parts of diethylene glycol mono- 4 ethylether. .After cooling, the reaction solution is poured into 250 parts ofwater and. exhaustively extracted with ether. The basic portions areremoved from the ethereal solution by extracting four times with diluteacetic acid- The combined acid extracts are made alkaline and the basewhich precipitatesis taken up iniethe'r. After drying, the ethersolution is concentrated .and the residue is recrystallized frompent-ane. The S-(ymethylaminopropylidene). 10,11dihydro-5H-dibenzo[a,d]cycloheptene so obtained melts at 58.

melts at 217.

The hydrolysis of-the urethane can also be performed in SO parts ofdiethylene glycolor 8O parts of ethylene glycol instead of the 50 partsof diethylene glycolimonoethyl ether- (b) In the same .manneras abovestarting :from 5-('ydimethy-lamino propylidene) -5H-dib'enzo [a,d]cyclohep-- tene in place .of 5-('y-dimethylamino-propylidene)-10,11-

dihydro-5H-dibenzo[a,d] cycloheptene, 5-' (-N'-carbethox-' 1ymethylamino)-propylidene SHE- dibenzo[a,d] cyclohep tene, which boilsat 185" under 0.02 mm. pressure isob' tained. From this,5-('y-methylamino-propylidene)-5H- dibenzo [-a,d]cyclohep'tene isobtained, the hydrochloride of which, after crystallisation fromanhydrous ,ethanol/ ether, melts at 182l.l84'.

Example 2 in lieu of 50 partsiof diethylene glycol'monoethyl ether inthe hydrolysis of the methane, and refluxing for 48 hours. Similarresults as in Example 1 are obtained.

I claim:

1. A compound of the formula,

O Ac. II I wherein X is a member-selected from the group consisting of--CH -CH and--CH=CHi'- and Ac .is a member selectedfrom the groupconsisting of lower alkoxy carbonyl, benzyloxy carbonyl, chlorocarbonyland lower alkanoyl.

2.. 5 -(y-[N-ethoxycarbonyl N-- methyl'amino]-propylidene)-l0,1.1-dihydro-5Hdibenzo [a,d] cycloheptene 3. 5 ('y [Nmethoxycarbonyl N methylamino1- propylidene)-5H-dibenzo[a,d]cycloheptene.

4. .5 [N- ethoxycarbonyl N" methylamino]-' propylidene).-5H-dibenzo.[-a,d] -cyc1oheptene.-

N 0 references cited.

LORRAINE A.=WEINBERGER, Primary Examiner. L. A. .THAXTON, AssistantExaminer.

(Yield, rate 82% based on the weight of the above urethanezderivativ'e.)The hydrochloride prepared with alcoholic hydrochloric acid Example 1is=repeated, but using parts of ethanol.

1. A COMPOUND OF THE FORMULA